Involvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I).

OR

Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma).

II

Involvement of two or more lymph node regions on the same side of the diaphragm (II).

OR

Localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of regions involved may be indicated by a subscript Arabic numeral, for example, II3

III

Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, IIIS). Splenic involvement is designated by the letter S.

IV

Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.

OR

Isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.

The Ann Arbor staging system is commonly used for patients with NHL.[1,2] In this system, stage I, II, III, and IV NHL can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without. The B designation is given to patients with any of the following symptoms:

Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.

Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.

The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Table 2. Notation for Identification of Sites

N = nodes

H = liver

L = lung

M = marrow

S = spleen

P = pleura

O = bone

D = skin

Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy.

For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be CS IIA, PS IVA(H+)(M+).

A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:

Age.

Performance status (PS).

Tumor size.

Lactate dehydrogenase (LDH) values.

The number of extranodal sites.

To identify subgroups of patients most likely to relapse, an international prognostic index was compiled for 2,031 patients with aggressive NHL.[3] After validation by several cancer centers (NCT00003150),[4,5] the major cooperative groups used this index in the design of new clinical trials. The model has been simple to apply, reproducible, and has predicted outcome even after patients have achieved a complete remission. The model has identified five significant risk factors prognostic of overall survival (OS): age (<60 years vs. >60 years), serum LDH (normal vs. elevated), PS (0 or 1 vs. 2–4), stage (stage I or stage II vs. stage III or stage IV), and extranodal site involvement (0 or 1 vs. 2–4).

Patients with two or more risk factors were shown to have a less than 50% chance of relapse-free and OS at 5 years. This study also identified patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system, liver, lung, and spleen. Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[3] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[6,7]